The proposed studies will explore the possibility that specific polymorphic epitopes on Ia molecules play a major role in determining susceptibility to rheumatoid arthritis as evidenced by the association with DR4. Underlying this project is the hypothesis that Ia molecules themselves have an intermediary role, and that the functionally important components of the molecule are specific epitopes. The question of the meaning of DR4-negative rheumatoid arthritis patient will be addressed and the possibility explored tht certain disease related epitopes on Ia molecules of these individuals are shared with molecules encoded by the specific DR4 haplotypes associated with RA. Moreover, how these epitopes are expressed and function will begin to be approached in individuals with rheumatoid arthritis as well as by using T cell hybridomas and clones. Extensive reliance will be placed on the interrelated techniques of molecular immunology and molecular biology to gain detailed insight into the relation between the complexity of the Ia system and susceptibility to rheumatoid arthritis. The resulting information will be applied to continuing studies on rheumatoid arthritis patients in an effort to more fully understand its significance in clinical terms and in better delineating the exact role of certain immunologic alterations in the pathogenesis of rheumatoid arthritis.